This invention relates to a method for the chemical synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol.
Both the D and L enantiomers of 1,4-dideoxy-1,4-imino-arabinitol are known compounds. They can be described alternatively as analogues of furanose sugars or as polyhydroxylated pyrrolidines.
Analogues of sugars, in which the ring oxygen has been replaced by nitrogen and the anomeric oxygen has been removed, usually.sup.1 but not always.sup.2 cause inhibition of the enzymic hydrolysis of the corresponding glycosidic bond. Although a number of naturally occurring analogues of hexoses containing six or more carbon atoms have been reported.sup.3, nitrogen analogues of only two pentoses, 2-deoxyribose and D-arabinose, have so far been isolated as natural products and these are pyrrolidine rather than piperidine derivatives. CYB3 (1), an analogue of 2-deoxyribose, was isolated from Castanospermum australe.sup.4 although, as yet, no significant biological activity has been described. Nectrisine (2),.sup.5 an imine nominally derived from dehydration of 4-amino-4-deoxy-D-arabinose, is an immunomodulator isolated from a fungus which shows potent inhibition of .alpha.-glucosidase and .alpha.-mannosidase activity..sup.6 DAB1 [1,4-Dideoxy-1,4-imino-D-arabinitol] (3), isolated from both Angylocalyx boutiqueanus.sup.7 and Arachniodes standishii,.sup.8 is a powerful inhibitor of yeast .alpha.-glucosidase.sup.9 and also inhibits different mouse gut dissacharidases to different degrees..sup. 10 Some studies on the mechanism of insect antifeedant activity of DAB1 have been reported;.sup.11 additionally, compounds such as DAB1 may be carcinogenic to rodents..sup.12 Also DAB1 inhibits the hydrolysis of sinigrin and progoitrin by thioglucosidases from mustard and the cabbage aphid, Brevicoryne brassicae..sup.13 DAB1 also inhibits phloem unloading and/or utilization of sucrose, resulting in insufficient sucrose transport from cotyledons to roots and hypocotyls. .sup.14 ##STR1##
The structure of DAB1 (3) was established by synthesis of both DAB1 and its enantiomer LAB1 (4) from L-arabinose.sup.15 and from D-xylose..sup.9,16 other syntheses of DAB1 and its stereoisomers have been reported from carbohydrate.sup.17 and other chiral pool starting materials,.sup.18 by sequences involving the use of aldolases as the key step,.sup.19 and by other methods..sup.20 LAB1 (4) was shown to be a potent inhibitor of the .alpha.-L-arabinofuranosidase III of Monilinia fructigena;.sup.21 although LAB1 is a much weaker inhibitor of yeast .alpha.-glucosidase than is the natural product DAB1, LAB1 is a much more powerful inhibitor of some mouse gut .alpha.-glucosidases than is DAB1;.sup.22 molecular modifying studies have been used to account for the observation that LAB1 is about ten times more powerful an inhibitor of sucrase than DAB1.sup.23. A number of polyhydroxylated nitrogen heterocycles were screened as agents for the inhibition of HIV-induced syncthia formation,.sup.24 of which LAB1 was among the most powerful antiviral agents..sup.25 Derivatives of LAB1 have also been shown to have antiviral activity..sup.26
The use of LAB1 as a strong inhibitor of human immunodeficiency virus (HIV) is further disclosed in U.S. Pat. No. 5,089,520, and its use as an intermediate in the synthesis of antiviral derivatives is disclosed in U. S. Pat. No. 4,876,268.